Neuropsychiatric systemic lupus erythematosus (NPSLE) is a life-threatening disorder and early diagnosis and proper treatment are critical for the management of patients with this disease. NPSLE can manifest as a range of neurological and psychiatric features, which are classified using the ACR case definitions for 19 neuropsychiatric syndromes . Approximately one-third of all NPSLE events in patients with SLE are primary manifestations of SLE-related autoimmunity, with seizure disorders, cerebrovascular disease, acute confusional state and neuropathy being the most common. Such primary NPSLE events are a consequence either of autoantibodies and inflammatory mediators, or of microvasculopathy and thrombosis. Diagnosis of NPSLE requires the exclusion of other causes, and clinical assessment directs the selection of appropriate examinations. These examinations include measurement of autoantibodies, analysis of cerebrospinal fluid, electrophysiological studies, neuropsychological assessment and neuroimaging to evaluate brain structure and function. This chapter reviews the important key points for the correct diagnosis and the differential diagnosis.